Systemic lupus erythematosus (SLE) is an autoimmune disease involving multiple organs. Through the involvement of the kidneys in the autoimmune inflammatory process lupus glomerulonephritis is a major cause of morbidity and mortality in this disease (Alarcon-Segovia D. In: Primer on the Rheumatic diseases. Ed. Schumascher H. R. Arthritis Foundation, Atlanta, Ga., (1988) pp. 96-100).
Serologically, the disease is characterized by the occurrence of a variety of autoantibodies in the serum, of which the most prominent are the anti-DNA auto antibodies (Naparstek Y et al Annu. Rev. Immunol. (1993) 11 79-104). Although low titers of anti-DNA antibodies may occur in various inflammatory and autoimmune diseases, high levels are found mainly in SLE, and the combination of high anti-DNA antibodies with low complement levels is virtually diagnostic of SLE (Wallace D. J. et al In: Dubois' Lupus erythematosus. Lea and Febiger, Philadelphia, 1993).
The binding of immunoglobulins to the glomerular basement membrane (GBM) has been shown by the staining of kidneys derived from lupus patients or lupus strains of mice (Wallace D. J. et al supra). It has also been shown that anti-DNA antibodies eluted from the kidneys of a lupus patient as well as from MRL/1pr/1pr mice cross react with sulfated glycosaminoglycans whereas the serum anti-DNA antibodies do not show this cross reactivity (Naparstek Y et al Arthritis Rheum. (1990) 33, 1554-1559). These results have suggested that extracellular matrix (ECM) play a role in pathogenesis of lupus as the target for the nephritogenic autoantibodies.
Temmat R. M. et al J. Autoimmun. (1990) 3 531-545, discloses the cross reaction of components of the ECM, like laminin and heparin with murine monoclonal anti-DNA antibodies.
EP Patent Application EP 670,495 discloses the presence of anti-ECM antibodies in the urine of patients with active lupus. Furthermore this patent application discloses the cross reaction of these antibodies with a 200 kDa laminin component of the ECM, and an assay for SLE based on the detection of these anti ECM/laminin antibodies in urine.
R38 is a peptide sequence isolated from the C-terminal region of the mouse laminin .alpha. chain (residues 2890-2910 according to Skubitz et al., J. Cell Biol (1991)115 1137-1148, or residues 2851-2871 according to Sasaki M. et al., J. Biol. Chem. (1988) 263, 16,536-16,544). It is located at the junction of the globular domains of the fourth and fifth loops (peptide GD-2 in Skubitz et al. J Cell Biol (1991) 115 1137-1148) and is comprised of the following amino-acid sequence:
KEGYKVRLDLNITLEFRTTSK (SEQ ID NO. 1)
Current SLE therapy is limited to corticosteroids which suppress the over-reactive immune system. This therapy is not specific and its inevitable side effects may themselves be fatal. Furthermore, immunosuppressive therapy is complicated and its initiation is based on a combination of clinical symptoms, blood serological tests and kidney biopsy. There is therefore a need for a more specific therapy for SLE that will not be associated with the side effects of the immunosuppresive agents as well as a more specific and less invasive assay for the evaluation of disease activity. Indeed a recent review (The Lancet (1995) 310 1257-1261) stated that blood tests though useful in confirming diagnosis of SLE are "less useful in monitoring disease activity."
None of the above mentioned references disclose the treatment of systemic lupus erythematosus by the administration of the R38 peptide or analogs thereof. Moreover none of the above mentioned references disclose the use of R38 peptide in a diagnostic test for the disease or in monitoring disease activity. The contents of all these patents and all literature references referred to above are hereby incorporated by reference in their entirety.